1. Field of the Invention
This invention relates to carboxylic acids and the derivative compounds thereof which have a Matrix Metalloproteinases (hereinafter shortened to MMPs) inhibitory function or the pharmaceutically acceptable salts thereof and the production method thereof; and further relates to a medicine containing said carboxylic acids, derivative compounds thereof or the salts thereof.
2. Description of the Prior Art
The MMPs are zinc dependent, calcium requiring enzymes that are involved in the degradation of extra cellular matrix. Under normal physiological conditions, the expression of the constitutive MMPs is low, and regulated by naturally occurring inhibitors termed TIMPs (tissue inhibitor of metalloproteinases). However, under pathological conditions such as rheumatoid and osteoarthritis, MMPs expression in cartilage is disregulated and results in over expression of MMPs which are not controlled by constitutive TIMPs. The level of the MMPs is high with enzymic activity and exceeding the level of the TIMPs. This condition leads to a loss of proteoglycan and collagen (J. Trzaskos, et al., Acta. Onthopaedica Scandinavia, 66, 150 (1995)).
In addition, MMPs inhibitors are effective on treatment for corneal ulceration and tumor progression (R. P. Beckett, et al., D.D.T., 1, 16 (1996)), and MMPs are playing important role in the pathogenesis of arteriosclerosis and restenosis after percutaneous transluminal coronary angioplasty (PTCA) (C. M. Dollery, et al., Circ. Res., 77, 863 (1995)). It is therapeutically useful to control the increased MMPs by MMPs inhibitors under these pathological conditions. Recently, a review of MMPs inhibitors has been published (R. P. Beckett, et al., D.D.T., 1, 16 (1996)).
3. Problems to be Solved by the Invention
Though many reported MMPs inhibitors had excellent in vitro activity, these compounds had poor oral bioavailabilities. For example, the compounds had been administered by intrapleural administration (Drug News & Perspectives, 8 (4), 247, (1995)) or eye drops (Drug of the Future, 18, 1101 (1993)).
The object of the present invention is the provision of pharmaceutical compositions useful as MMPs inhibitors being capable of oral administration and a production method thereof.